Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD-specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co-expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids and medium/long-chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co-expression network analysis of the AMP-AD brain RNA-seq data suggests the CPT1A- and ABCA1-centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short-chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large-scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis.

中文翻译：

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综合代谢组学-基因组学方法揭示了阿尔茨海默病的关键代谢途径和调节因子

代谢物是细胞过程的生化产物，可用于测量与阿尔茨海默病 (AD) 发病机制相关的生化途径的变化。然而，全身代谢异常与 AD 发病机制之间的关系尚不清楚。在这项研究中，我们的目标是通过分析 AD 遗传、转录组、代谢组和蛋白质组数据的综合系统生物学框架来识别 AD 特异性代谢组变化及其潜在的上游遗传和转录调节因子。阿尔茨海默病神经影像计划 (ADNI) 血液代谢组数据的代谢物共表达网络分析显示，短链酰基肉碱/氨基酸和中/长链酰基肉碱与 AD 临床结果（包括情景记忆评分和疾病严重程度）最相关。对 ADNI 血液和加速药物合作阿尔茨海默病 (AMP-AD) 计划大脑中基因表达数据的整合表明，ABCA1 和 CPT1A 参与 AD 中酰基肉碱和氨基酸的调节。AMP-AD 大脑 RNA-seq 数据的基因共表达网络分析表明，以CPT1A和ABCA1为中心的子网络分别与神经元系统和免疫反应相关。ABCA1基因表达和脂联素蛋白（ABCA1 的调节因子）的增加与 ADNI 中 AD 中短链酰基肉碱和胺的减少相对应。总之，我们对 AD 大规模多组学数据的综合分析系统地识别了 AD 中的新代谢物及其潜在调节因子，这些发现不仅为开发 AD 敏感和特异的诊断生物标志物，而且还为确定 AD 发病机制的新分子机制铺平了道路。 。